19-12893531-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000159.4(GCDH):c.383G>A(p.Arg128Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.383G>A | p.Arg128Gln | missense_variant | 6/12 | ENST00000222214.10 | NP_000150.1 | |
GCDH | NM_013976.5 | c.383G>A | p.Arg128Gln | missense_variant | 6/12 | NP_039663.1 | ||
GCDH | NR_102316.1 | n.546G>A | non_coding_transcript_exon_variant | 6/12 | ||||
GCDH | NR_102317.1 | n.799G>A | non_coding_transcript_exon_variant | 5/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GCDH | ENST00000222214.10 | c.383G>A | p.Arg128Gln | missense_variant | 6/12 | 1 | NM_000159.4 | ENSP00000222214 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251442Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135912
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461602Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727118
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glutaricaciduria, type I (MIM#231670). Dominant-negative has also been suggested as a mechanism for this gene, however, there is currently limited evidence demonstrating this (GeneReviews). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, N-terminal domain (PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg128Gly) variant has informative conservation and has been previously been reported as a pathogenic variant (PMID: 9711871). (N) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals with glutaricaciduria, type I (MIM#231670) (PMIDs: 18459892; 10699052; 21176883; 31062211; 32508882) (SP). 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 08, 2022 | Variant summary: GCDH c.383G>A (p.Arg128Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251442 control chromosomes (gnomAD). c.383G>A has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1, including at least 3 homozygotes (Zschocke_2000, Boy_2017, Tamhankar_2020) and several compound heterozygotes (e.g. Zschocke_2000, Mushimoto_2011, Boy_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: two have classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 128 of the GCDH protein (p.Arg128Gln). This variant is present in population databases (rs755586631, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 10699052, 15505393, 19433437, 21176883, 28438223). ClinVar contains an entry for this variant (Variation ID: 189063). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCDH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at